Obesity/diabetes adversely impact myocardial ischemia/reperfusion (MI/R) injury by incompletely understood mechanisms. Visceral adipocyte (ADp) dysfunction contributes to remote organ injury. However, the molecular link(s) between dysfunctional ADp and increased MI/R injury remain(s) unidentified. Extracellular vesicles, particularly exosomes (Exo), are systemic messengers mediating inter-organ communication. However, whether and how diabetes may alter Exo-mediated ADp-heart communication remain unknown. Our preliminary experiments demonstrate that diabetes causes significant pathologic alterations in both donor (ADp) and recipient (cardiomyocyte, CM) cells, increasing MI/R injury. This application will test a hypothesis that diabetic alteration of Exo-mediated ADp to heart communication is a novel mechanism exacerbating post-MI cardiac remodeling. Three specific aims will be addressed. SA1 will clarify the downstream mechanisms responsible for diabetic ADp Exo exacerbation of acute MI/R injury. We revealed for the first time that miR-130b-3p is a common molecule significantly increased in diabetic ADp Exo and diabetic patient serum. MiR-130b-3p mimics exacerbated MI/R injury, whereas miR130b-3p inhibitor mitigated acute MI/R injury. Experiments in this aim will 1) define ADp as the cellular source of miR-130b-3p in the diabetic heart; and 2) identify the downstream molecular targets mediating the pro-apoptotic effect of miR-130b-3p. SA2 will identify mechanisms responsible for increased uptake of ADp Exo by diabetic CM. Preliminary data suggest that reduced Cav3 expression and increased Cav3 nitration in the diabetic heart is likely responsible for the loss of ADp Exo transmembrane signaling and promotion of ADp Exo uptake by CM. Combining genetic and pharmacologic approaches, we will rigorously test a novel hypothesis that Cav3/AdipoR1 signaling complex integrity is critical in determining the fate of ADp Exo. Diabetic dissociation of cardiac Cav3/AdipoR1 switches AdipoR1 from a receptor mediating ADp- derived, adiponectin-rich Exo initiated signaling in non-diabetic CM to a vehicle facilitating diabetic ADp Exo entry within CM. SA3 will test a hypothesis that interventions blocking Exo mediated ADp-CM communication are novel therapy against diabetic exacerbation of post-MI remodeling and HF. Preliminary data demonstrate that intramyocardial injection of diabetic ADp Exo exacerbates acute MI/R injury in non-diabetic mice, whereas Exo production inhibition attenuates MI/R injury in diabetic mice. Experiments in this aim will determine whether ADp-specific miR-130b-3pKO or CM-specific Cav3OE is effective in protecting the diabetic heart from excessive post-MI cardiac remodeling. To increase the translational value of our findings, we will determine whether administration of miR-130b-3p inhibitor or peroxynitrite decomposition catalyst effectively protects against diabetic ADp Exo-mediated augmented cardiac remodeling and HF. Successful completion of these studies will reveal the molecular mechanisms responsible for diabetic ADp Exo-induced cardiac injury, spawn interventions targeting Exo mediated ADp-CM communication, and ultimately protect against cardiac diabetic MI/R injury.